EPIDEMIOLOGY
OF CUTANEOUS
MALIGNANT
MELANOMA
IN WESTERN
SWEDEN
Magdalena Claeson, MD
Department of Dermatology and Venereology,
Institute of Clinical Sciences,
Epidemiology of cutaneous malignant melanoma in Western Sweden © Magdalena Claeson, MD, 2016, by magdalena.claeson@vgregion.se ISBN: 978-91-628-9933-2 (PDF) 978-91-628-9934-9 (Print) http://hdl.handle.net/2077/47402 Printed in Gothenburg, Sweden, 2016, by INEKO AB
Book layout by Gudni Olafsson Cover image: The archipelago
of Western Sweden. (www.pixabay.com)
“AN OUNCE OF
PREVENTION IS WORTH
A POUND OF CURE.”
CONTENTS
ABSTRACT 7 SAMMANFATTNING PÅ SVENSKA 9 LIST OF PAPERS 11 ABBREVIATIONS 13 DEFINITIONS IN SHORT 15 1. INTRODUCTION 17 1.1 EPIDEMIOLOGY OF MELANOMA 171.2 CAUSES AND RISK FACTORS 20
1.3 PREVENTION 27
1.4 STAGING AND CLASSIFICATION 35
1.5 PROGNOSIS 39
1.6 MANAGEMENT 40
1.7 HEALTH CARE ECONOMICS AND
HEALTH SYSTEMS MANAGEMENT 41
2. AIMS 47
3. METHODS 49
3.1 THE SWEDISH CANCER REGISTRY 49
3.2 THE SWEDISH MELANOMA REGISTRY 49
3.3 THE SWEDISH CAUSE OF DEATH
REGISTRY 50
3.4 NATIONELL MILJÖHÄLSOENKÄT 2007
– THE SUN EXPOSURE SURVEY 50
3.5 STUDY DESIGN 51 3.6 ETHICAL CONSIDERATIONS 54 4. RESULTS 57 4.1 STUDY I 57 4.2 STUDY II 57 4.3 STUDY III 58 4.4 STUDY IV 58
5. DISCUSSION & METHODOLOGICAL
CONSIDERATIONS 61 5.1 STUDY I 61 5.2 STUDY II 62 5.3 STUDY III 63 5.4 STUDY IV 64 6. CONCLUSIONS 67 7. FUTURE PERSPECTIVES 69
7.1 GEOGRAPHICAL DIFFERENCES IN UVA
AND UVB RADIATION LEVELS 69
7.2 MULTIPLE PRIMARY MELANOMAS IN
RISK PREDICTION MODELS 69
7.3 PREDICTORS OF MORTALITY FOR THIN
MELANOMAS 69
7.4 FURTHER USE OF SYSTEM DYNAMICS 69
8. ACKNOWLEDGEMENTS 73
9. REFERENCES 77
10. PAPERS 91
I. INCIDENCE OF CUTANEOUS MELANOMA IN WESTERN SWEDEN, 1970–2007 II. MULTIPLE PRIMARY MELANOMAS:
A COMMON OCCURRENCE IN WESTERN SWEDEN
III. LETHAL MELANOMAS: A
POPULATION-BASED REGISTRY STUDY IN WESTERN SWEDEN FROM 1990-2014 IV. MODELLING THE FUTURE:
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
ABSTRACT
ABSTRACT
The incidence of cutaneous malignant mela-noma (melamela-noma) has been rising worldwide for the past decades, causing a major public health problem. The overall aim for this thesis was to study the epidemiology of melanoma in Western Sweden and to suggest secondary preventive interventions.In study I, data from the Swedish Cancer Registry demonstrated that the melanoma incidence in West-ern Sweden quadrupled among men and tripled among women between 1970-2007. Coastal areas and the city of Gothenburg showed a higher inci-dence than inland areas. Analysis of meteorological maps of Western Sweden and a sun exposure survey showed that this could be due to high annual average duration of sunshine and high sun exposure on holi-days abroad. In studies II and III, data from the Swed-ish Melanoma Registry and the SwedSwed-ish Cause of Death Registry were analysed. Study II showed that, during 1990-2013, 7.4% of all melanoma patients de-veloped multiple primary melanomas. Subsequent melanomas presented with a higher proportion of melanoma in situ. Study III demonstrated that thin melanomas (≤1 mm Breslow) constituted 55.2% of all invasive melanomas and accounted for 14.7% of all melanoma deaths, between 1990-2014. Signifi-cantly poorer survival was identified for ulcerated melanomas 0.26-1 mm Breslow and for non-ulcer-ated melanomas 0.76-1 mm Breslow. In study IV, a system dynamics computer model was developed that projected the number of future melanoma cases. The model compared five plausible future scenarios, showing that after ten years, improved overall secondary prevention would have resulted in a shift towards thinner melanomas.
This thesis concluded that the high incidence of melanoma in Western Sweden justifies a focus on preventive interventions to this area. Patients and
physicians need to be alerted about the risk of multi-ple primary melanomas. The identified subgroup of lethal thin melanomas suggests that these patients may benefit from closer surveillance in follow-up programmes. Lastly, system dynamics modelling proved to be a valuable tool, which can help policy-makers select the preventive interventions with the greatest impact.
Keywords: Cutaneous malignant melanoma, Epide-miology, Prevention, Incidence, Mortality, Multiple primary melanomas, Thin melanomas, System dy-namics modelling
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
Sweden
SAMMAN-FATTNING
PÅ SVENSKA
SAMMANFATTNING
PÅ SVENSKA
MELANOMEPIDEMIOLOGI
I VÄSTSVERIGE
Malignt melanom i huden blir allt vanligare i ljushya-de befolkningar runt om i värlljushya-den. Ökningen förklaras delvis av mer UV-exponering i befolkningen, t ex fritidsexponering för sol, förändrade klädvanor, solse-mestrar och solarier. Sverige tillhör de länder i världen som har allra högst incidens av melanom. Landet har också en mycket hög kostnad för hudcancervård, i förhållande till befolkningens storlek. Västsverige har sedan länge haft en av de högsta incidenserna av melanom i Sverige. Ökningen av melanom har proportionellt sett varit störst bland de tunna mela-nomen (≤1 mm Breslowtjocklek). Tunna melanom har i allmänhet en god överlevnadsprognos, men en (oidentifierad) undergrupp av dessa tumörer har ändå potential att orsaka patientens död. Det är också sedan tidigare känt att en del patienter utvecklar flera primära melanom (multipla primära melanom). Det övergripande syftet med den här avhandlin-gen var att beskriva melanomepidemiologin i Västsverige, och att föreslå sekundärpreventiva åtgärder. I delarbete I analyserades data från det svenska cancerregistret. Förekomsten av invasiva melanom i Västra Götalandsregionen fyrdubblades bland män och tredubblades bland kvinnor från 1970-2007. Kustkommuner och Göteborg hade en högre incidens än inlandskommuner. Analys av meteorologiska kartor och en solvanestudie från Socialstyrelsen visade att detta kan bero på fler sol- timmar/år längs kusten, och på att dessa befolkning-ar vbefolkning-ar mer utsatta för solexponering vid semestrbefolkning-ar utomlands.
I delarbete II analyserades data från kvalitetsreg-istret för melanom. Delarbetet visade att 7,4 % av alla melanompatienter i Västra Götalandsregionen utvecklade flera melanom (multipla primära mela-nom) mellan 1990-2013. Det påföljande melanomet
var oftare ett melanom in situ (förstadium) jämfört med det första melanomet. Av de påföljande mela-nomen diagnostiserades 49 % inom tre år.
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
LIST OF
PAPERS
LIST OF PAPERS
This thesis is based on the following studies, re-ferred to in the text by their Roman numerals.
I. Claeson M, Andersson EM, Wallin M,
Was-tensson G, Wennberg AM, Paoli J, Gonzalez H. Incidence of cutaneous melanoma in Western
Sweden, 1970-2007. Melanoma research 2012;
22(5): 392-398.
II. Claeson M, Holmström P, Hallberg S, Gillstedt M, Gonzalez H, Wennberg AM, Paoli J. Multiple
primary melanomas: a common occurrence in Western Sweden. Accepted for publication in
Acta Derm Venereol.
III. Claeson M, Gillstedt M, Whiteman DC, Paoli J.
Lethal melanomas: a population-based registry study in Western Sweden from 1990-2014.
Sub-mitted.
IV. Claeson M, Hallberg S, Holmström P, Wenn-berg AM, Gonzalez H, Paoli J. Modelling the
future: System dynamics in the cutaneous malignant melanoma care pathway. Acta Derm
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
Sweden
ABBREVI-
ATIONS
ALM Acral lentiginous melanoma a.k.a acrolentiginous melanoma
CI Confidence interval
CMM Cutaneous malignant melanoma (melanoma)
COX Cox proportional hazards regression analysis
LMM Lentigo maligna melanoma
NM Nodular melanoma
OR Odds ratio
RR Relative risk
SD System dynamics
SSM Superficial spreading melanoma
UV Ultraviolet (radiation)
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
DEFINITIONS
IN SHORT
DEFINITIONS IN SHORT
AJCC staging system The American Joint Committee on Cancer staging manual for cutaneous malignant melanoma, updated with a seventh edition in 2009.
Breslow thickness The distance between the upper layer of the epidermis and the deepest point of penetration of a malignant melanoma (measured in millimetres). Named after the pathologist Alexander Breslow. Clark level The level of anatomical invasion of a melanoma. Named after the pathologist and dermatologist Wallace H. Clark. Jr.
Fitzpatrick scale A numerical classification of human skin pigmentation, ranging from type I-VI. Developed by dermatologist Thomas B. Fitzpatrick.
Melanoma incidence rate
The number of new melanomas occurring in a population during a given time period (typically expressed per 100,000 person-years).
Melanoma mortality rate The number of deaths from melanoma in a population during a given time period (typically expressed per 100,000 person-years).
TNM staging system
Magdalena Claeson
Epidemiology
of cutaneous
malignant
melanoma
in Western
Sweden
INTRO-
DUCTION
01
INTRODUCTION
1.1 EPIDEMIOLOGY OF
MELANOMA
1.1.1 INCIDENCE
International demographicsThe incidence of cutaneous malignant melanoma (melanoma) has been rising in most fair-skinned populations around the world for the past decades, causing a major public health problem (1, 2). The
highest incidence rates are found in New Zealand and Australia, followed by Switzerland, the Nether-lands and the Scandinavian countries of Denmark, Norway and Sweden (3). The incidence rates of
mel-anoma are approximately twice as high in New Zea-land and Australia, as compared to Sweden. In 2012, this was described by the International Agency for Research of Cancer, with incidence rates of around 36 and 35 per 100,000 person-years (World standard population year 2000) for New Zealand and Austra-lia, respectively (3). The corresponding incidence for
Sweden was 18 per 100,000 person-years.
It is well known that melanoma incidence follows a latitude gradient. The latitude affects the sun’s angle, and thus the level of UV radiation. As an example of this, high incidence rates are reported in fair-skinned populations living at lower latitudes in the United States, Australia and New Zealand, compared to populations living at higher latitudes in those countries (4). In Europe, the gradient is not
continu-ous, but decreases with increasing latitude until ap-proximately 50° North, where the countries Belgium and Luxembourg are situated. At this parallel, the incidence reverses and increases in the Netherlands and in Scandinavia (1).
The cause of the steep, worldwide increase of mel-anoma incidence has been an area of much debate
(5). The increase has been partly attributed to a true
increase in melanocytic tumours, due to increased
intermittent sun exposure. Outdoor recreational activities, sun-holidays and sunbed use are all ex-amples of intermittent sun exposure. The increasing incidence has also been proposed to be a result of pressure from early detection, leading to overdiag-nosis. Improved early detection of melanoma in turn, is perceived as an outcome of improved sur-veillance techniques and growing awareness of skin cancer in the public (5-7). Further, the increase has
been attributed to diagnostic drift (5).
However, after continuing increases in melanoma rates in fair-skinned populations for decades, recent encouraging studies have shown that Australia is ex-periencing a decline, with an annual percentage inci-dence change of -0.68 between the years 2005-2011
(2, 8). See Figure 1 for an overview of incidence rates
Figure 1. Age-standardized incidence of melanoma (US standard population year 2000) from 1982-2011 and annual percentage change in six populations. (a) US whites. (b) United Kingdom. (c) Sweden. (d) Norway. (e) Australia. (f) New Zealand. APC, annual percentage change; ASR, age standardized rate.
Reprinted from the Journal of Investigative
Dermatology, 2016; 136(6), Whiteman DC et al, The Growing Burden of Invasive Melanoma:
Projections of Incidence Rates and Numbers of New Cases in Six Susceptible Populations through 2031, pages 1161-71. Copyright (2016) with permission from Elsevier (9).
Swedish demographics
Today, melanoma is the sixth most common type of cancer among men in Sweden, and the fifth most
common among women (10). Of all Swedes, 2.2%
of men and 2.1% of women will develop a melano-ma before the age of 75 (11). This can be compared
to breast cancer, developing in 10.1% of Swedish women and prostate cancer, developing in 11.8% of Swedish men, before the age of 75. Melanoma, to-gether with other skin cancers (with an exception of basal cell carcinoma), is the fastest increasing type of cancer, representing 17% of the total cancer cases in Sweden (10). The incidence of melanoma specifically
is also rapidly increasing, with an annual percentage increase of over 6%, which is a worrisome trend (12).
In 2014, the incidence rates of melanoma for men and women were 40 and 35 per 100,000 person-years, respectively (Swedish standard pop-ulation year 2000) (10). That year, 1,855 men were
registered in the Swedish Cancer Registry, having a total of 1,912 melanomas. Correspondingly, 1,813 women were registered having a total of 1,840 mel-anomas. In addition to the invasive tumours, 3,212 melanomas in situ were registered (1,639 for men, 1,573 for women).
Melanoma incidence varies with age, but melanoma can occur at any age. However, the tumour is exces-sively uncommon in children. In Sweden, only 69 cases of melanoma were registered in patients <20 years old between 2000-2009. Most of these pa-tients were adolescents, aged 15-19 (13). In adulthood,
melanoma incidence increases with age. In contrary to many other types of cancer, mainly affecting older adults, melanoma is infamous for affecting young and middle-aged persons. Though relatively com-mon in the younger age group, the median age at diagnosis in 2014 was 68 years for men and 63 years for women (14).
Apart from a latitude gradient for the melanoma incidence worldwide, there are also regional north-south geographical differences within Sweden. The incidence level is almost twice as high in the health care regions of Western Sweden and South-ern Sweden, as compared to the NorthSouth-ern region
(6). Since decades, Western Sweden has had one of
the highest melanoma incidences in the country
(13). The factors contributing to the high incidence
in Western Sweden have long been discussed, but no definite answers have been provided. Apart from higher UV radiation levels in Western Sweden com-pared to Northern Sweden, associating factors like socioeconomic status, genetic mutations specific to the region and high nevus counts in the population have been proposed (15-18).
Future projections for melanoma incidence
Several previous studies have attempted to prog-nosticate the future number of melanomas for Sweden (2, 19), at around the same time as Study IV
of this thesis was published. There is certainly no ease in the melanoma burden projected for Sweden. On the contrary, one study from the Southern Swe-den health care region estimates an increase in the number of melanoma cases with 75%, from 645 to 1,129 between the years 2008 and 2022 (19). Another
study estimates a continuous increase of incidence for Sweden as a whole, on-going until at least 2022-2026, taking the ageing population into account (2).
Knowledge of a coming incidence increase is im-portant for several reasons. First, it gives caregivers time to prepare for an increased health care demand. Further, policymakers can allocate resources for pre-ventive strategies to break trends.
Standardization of
incidence and mortality rates
1.1.2 MORTALITY
Melanoma is responsible for the vast majority of deaths due to skin cancer. World-wide, more than 55,000 persons were reported to have died from melanoma in the year 2012 (3). The mortality rates
for melanoma have also been rising in many coun-tries for the past decades, but slowly and to a much smaller extent than has incidence rates (2). The
high-est mortality rates in the world are found in New Zealand and Australia (3).
In Sweden, the annual percentage change of the mortality rate was low until the mid 1990s (+0.25% for the years 1982-1996), but then slowly started to increase (+1.80% for the years 1996-2011), standard-ized to the United States population in year 2000
(2). From 2002 until 2012, the number of women
ultimately succumbing to melanoma in Sweden has increased with 48%. The corresponding increase for men was 33% (11). Although the increase in
melano-ma deaths has been higher among women during the last years, the overall melanoma mortality is still higher for men than for women. In Sweden, the mortality rates in 2014 were 6.4 for men and 3.9 for women per 100,000 person-years (Swedish stan-dard population year 2000), which corresponded to 292 men and 214 women dying from the disease during that year.
1.2 CAUSES AND
RISK FACTORS
This chapter summarizes in short the pathophys-iology of melanoma, as well as the main factors increasing the risk of melanoma development. Risk factors have historically been analysed as indepen-dent variables, illustrated by the subheadings in the chapter below. However, it is becoming increasingly common to combine risk factors into risk predic-tion models for skin cancer (20). Such models will
undoubtedly be of importance in the future, both in clinical practice and in public health practice.
1.2.1 PATHOPHYSIOLOGY
Melanoma develops through out-of-control growth of pigment-containing melanocytes in the skin, forming a malignant skin neoplasm. The process is likely to be multifactorial, involving UV light exposure and genetic predisposition, resulting in a
build-up of genetic mutations in the melanocyte. Next, activation of growth stimulatory pathways, inactivation of tumour suppressor genes and a defective DNA repair system lead to melanoma cell proliferation. Further in the tumour evolution there is angiogenesis, tumour invasion of the deeper layers of the skin and lack of immune response that causes metastasis (21).
In the lately postulated divergent pathway model it has been hypothesized that melanoma develops through two divergent pathways (22, 23):
1. In people with low nevus count, cumulative sun exposure causes late-onset melanoma predomi-nantly on the head and neck. Head and neck mel-anomas are anatomic locations related to patterns of chronic sun damage. The
melanoma subtype associ-ated with chronic sun dam-age is often characterized by initial mutations in the NRAF, NF1, KIT and
BRAF-nonV600E genes.
2. In people with high nevus count, smaller doses of intermittent sun exposure cause early-onset melano-ma predominantly on the trunk and limbs. The trunk and limbs are anatomic lo-cations related to patterns of intermittent sun expo-sure. This melanoma sub-type is often characterized by initial genetic mutations in BRAFV600E.
Previously it was believed that melanomas arise solely within a pre-existing nevus. However, contemporary re-search shows that only about one of four melanomas devel-op within a pre-existing lesion
(24-26). Correspondingly, three
of four melanomas develop in
clinically normal skin (“de novo” melanomas).
1.2.2 UV LIGHT EXPOSURE
UV radiation is separated into UVA (320-400 nm), UVB (290-320 nm) and UVC (100-290 nm). UVC is absorbed by the ozone layer and is therefore not a potential source of radiation on earth. Today, there is consensus about UV light exposure being the major cause of melanoma (see Figure 2 and 3) (27). Since
2009, the World Health Organization classifies UVA, UVB and sunbeds as carcinogenic (28).
Some evidence for UV light exposure being the ma-jor cause of melanoma follows below (27, 29-31):
1. UVA and UVB have been confirmed to cause DNA damage and are involved in melanoma develop-ment. However it is still unknown what specific wavelengths that are involved (1).
2. Fair-skinned populations have a higher incidence of melanoma (31).
3. There is an association between sun exposure and the risk of melanoma, with relative risks (RR) increasing for early childhood sunburns (RR=2.24 (95%CI: 1.73-2.89)), sunburns during life (RR=2.08 (95%CI: 1.70-2.55)) and intermittent sun exposure (RR=1.61 (95%CI: 1.31-1.99)) (27).
Also, a recent review has shown that the total UV exposure during life, measured by the objective presence of solar keratoses on the head and neck, is associated with increased risk of melanoma (31).
In the Western world, attitudes toward sunbathing have changed during the last centuries. Earlier, avoidance of the sun and a fashion that encouraged a pale white skin was the norm among aristocrats. A suntan, on the other hand, was the mark of a la-bourer. But in the late 1800s, outdoor recreation ac-tivities and sport and tourist organisations started to form. Swimming and sunbathing was perceived as healthy for the body and soul and thus, going to the beach became popular around this period of time
(32). Following this motion, in the 1920s, the famous
Parisian fashion designer and businesswoman Coco Chanel made a suntan desirable and a symbol of a privileged life (33). Much of these attitudes towards a
sun-seeking behaviour are dominant also today. Further, sun holidays have become fashionable during the last half-century, which has increased the level of intermittent sun exposure in fair-skinned populations even more (34, 35). During the last century,
clothing habits have also changed, which probably has had an effect on the melanoma incidence. For in-stance, a study from Norway has shown that the inci-dence of melanoma on the breast of younger women increased after the habit of topless sunbathing was introduced in the 1970’s (36).
The ozone layer in the stratosphere protects the earth from UV radiation. Depletion of the ozone lay-er results in more UV radiation from the sun reach-ing the surface of the earth. As a result of the use of chlorofluorocarbons such as Freon, the total ozone decreased on a global scale in the 1960s and 1970s. However, contrary to public sentiment, the total ozone specifically over Sweden has remained large-ly unchanged during the last decades (37, 38). Thus,
the increase in skin cancer incidence in Sweden can-not be linked to the ozone layer. Today, the danger of global ozone depletion has hopefully been prevent-ed, with falling Freon levels in the atmosphere.
Sunbeds
Artificial sunbeds (also known as solariums, see
Figure 4) are devices that can be used to create a
cosmetic tan. They emit mostly radiation in the UVA spectrum, but also some UVB radiation (39). Sunbeds
increase the risk of melanoma significantly, with a lifetime exposure to more than 10 tanning sessions resulting in an odds ratio (OR) of 1.34 (95% CI: 1.05-1.71) (40). Also, first use of a sunbed before the age
of 35 has shown to be associated with a RR of 1.87 (95%CI: 1.41-2.48) (41).
Figure 4. Sunbed (also known as solarium) Photo: AdobeStock
There is a north-south gradient with high preva-lence of exposure to UV radiation from sunbeds in the populations in northern Europe, compared to southern Europe. A study from 2005, comparing sunbed use in five European countries, showed that participants from Sweden and the Netherlands had the highest cumulative exposure to sunbeds
(42). Further, a survey from the Swedish Radiation
Safety Authority from 2008 showed a rate for ever using sunbeds of around 50% among participating Swedes aged 18-24 years (13).
A sharp increase in the incidence of melanoma in Iceland during 1995-2002, resembling a melanoma epidemic, further supports the hypothesis that sunbed use increases the risk of melanoma (43). The
increase in Iceland was higher for melanomas on the trunk among young women, who also had the high-est records of sunbed use. The role of sunbeds in-ducing melanoma was additionally strengthened by the decline in melanoma incidence trends after the Icelandic health authorities introduced a campaign, discouraging sunbed use. The campaign focused on adolescent girls.
1.2.3 GENETICS
Around 8-12% of melanoma patients have a family history of melanoma (44). It is firmly established
that having a relative with melanoma is a risk factor for melanoma. The risk of melanoma development further increases when two first-degree relatives are affected (45). In Sweden, germline mutations have
been found in only 10% of the familial melanoma cases (15, 46). Germline mutations are constitutional,
occur in every cell of the body and can be inherit-ed. The high-risk gene that is best known today is CDKN2A (Cyclin-dependent kinase 2A). This gene is a regulator of cell division and it codes for two different proteins (p16 and p14). Previous research has shown a significantly increased RR of around 60 for developing a melanoma in carriers of CDKN2A mutations (47).
Several somatic mutations are found in the melano-ma tumour tissue. Somelano-matic mutations are acquired within a lifetime and are not inherited. The most common somatic mutation found in melanomas is in the BRAF oncogene, occurring in around
50% of melanomas. BRAFV600E mutations are
characteristically associated with melanomas on non sun-exposed anatomical locations in younger patients with a high nevus count (48).
Xeroderma pigmentosum is a very rare autosomal recessive disease, occurring in about 2.3 per million live births in Western Europe (49). The disease is
defined by an extreme sensitivity for sun exposure, resulting from a defect in the DNA repair system. One study has shown that Xeroderma pigmen-tosum patients <29 years of age have a more than 2000-fold increase of melanomas, compared to the general population (50).
1.2.4 SKIN TYPE
Skin types are classified according to the Fitzpatrick scale of human skin pigmentation (51). The
classifi-cation measures the response to UV radiation for different types of skin, ranging from skin type I (al-ways burns, never tans) to skin type VI (never burns, deeply pigmented skin). A meta-analysis has shown that people with skin type I and II are at significantly higher risk of melanoma compared to people who do not burn and who tan easily (RR=2.99 (95%CI: 1.75-5.12)) (44). Skin type is often, but not always,
correlated to phenotypic traits as blue or green eye colour, red hair and a tendency to freckle (51). These
phenotypic traits are also signs of constitutional UV-sensitivity, and have been shown to increase the risk of melanoma development in meta-analysis (44).
Melanoma is uncommon in people with darker skin types. For instance, though living in the same country and at the same latitudes, the incidence in the black population in the United States in 2011 was 1 per 100,000 person-years (the United States standard population year 2000), whereas the inci-dence of non-Hispanic whites was 22 per 100,000
person-years (52). However, in people of colour,
melanomas of the histopathological subtype acral lentiginous melanoma (ALM) are proportionally
more common (53). Unlike other histopathological
subtypes, ALMs do not seem to be caused by expo-sure to UV radiation (54).
1.2.5 MELANOCYTIC NEVI
with melanoma formation (24, 25, 55). It has been
es-tablished that the number of common melanocytic nevi is a risk factor for the development of melano-ma. A high nevus count has also been proposed as an indicator for previous sun exposure (55, 56). Thus,
sun exposure may independently cause both a high nevus count and an increased risk of melanoma de-velopment (57). A review of several studies showed a
significantly increased risk for persons with a very high nevus count (101-120 nevi), showing a pooled RR=6.89, in comparison with persons with very few nevi (0-15 nevi) (55). In conclusion, having a very
high number of nevi is considered a strong risk fac-tor for melanoma.
Several studies during the 1990s showed that clini-cally atypical nevi were associated with higher risk
of developing a melanoma (55). Nevertheless, the
clinical criteria for atypical nevi have serious flaws and it seems that the size of nevi and the number of these are probably a better and more objective way of estimating the risk of melanoma (58-60).
Lastly, congenital melanocytic nevi have an in-creased risk of progression to melanoma, although this is mainly related to congenital nevi of giant size
(61, 62).
1.2.6 MULTIPLE PRIMARY MELANOMAS
The risk of developing a subsequent primary mel-anoma is increased in patients diagnosed with a single primary melanoma. The subsequent primary melanoma occurs separately from the first melano-ma, and is not the equivalent of a metastasis. There are numerous risk factors identified for developing multiple primary melanomas, which to a large extent coincide with those for developing a single primary melanoma. Age, fair skin type, family histo-ry of melanoma and presence of many or large nevi have all been reported to be important risk factors for multiple primary melanomas (63-65). It has long
been debated whether multiple primary melanomas increase the mortality of melanoma, but recent stud-ies indicate this (66, 67).
Previous studies have shown that a percentage of 0.2-8.6% of patients with single primary melanomas
develop multiple primary melanomas (68). This
percentage varies, and one reason for this is that the
inclusion or exclusion of melanoma in situ varied between studies. A further reason is that some stud-ies were based in skin cancer clinics, with high-risk patients, and some others were population-based. A third reason to the variation in the proportion of patients with multiple primary melanomas, is the study length, since aging patients are more prone to develop subsequent melanomas. It is not unusual that multiple lesions are detected synchronously with the first melanoma, but detection can also occur during follow-up. Subsequent lesions are most common within the first years of follow-up after diagnosis of the initial melanoma (63, 65, 68-70).
Furthermore, patients who attend regular follow-up have been found to present with thinner melano-mas (according to Breslow thickness) than those who did not attend follow-up (71, 72).
In Sweden, during 1990-2008, 2.6% of the patients diagnosed with a single primary melanoma devel-oped one or more subsequent primary melanoma(s)
(14). This percentage increased to 3.2% during the
years 2009-2012. Analysing the entire time period from 1990-2014, over 4% of the melanoma patients were registered with multiple primary melanomas. However, the numbers above only included invasive melanoma.
1.2.7 IMMUNOSUPPRESSION
Immunosuppressant medication is obligatory in organ transplant recipients, to prevent organ rejec-tions. However, immunosuppression impairs the capacity of the human immune system to repair cells damaged by UV radiation, which can lead to the development of cancers. It has been estimated that 50% of all organ transplant recipients develop skin
cancer (73). Although immunosuppression is best
known to increase the risk of squamous cell carci-noma and basal cell carcicarci-noma, a meta-analysis has also shown a significantly increased risk of melano-ma, with a pooled estimated increased risk between 2 and 8 (73). More so, melanomas in organ transplant
recipients have been found to have a thicker depth of invasion according to Breslow and a lower surviv-al compared to non-transplant individusurviv-als (73).
Effective primary prevention interventions
The influential Community Preventive Services Task Force under the United States Department of Health and Human Services has conducted a systematic review of the effect of community inter-ventions to promote sun protection (79). There are
some examples of settings where sun protection interventions have shown sufficient evidence to be used. These include occupational outdoor set-tings, outdoor recreational and tourism settings and interventions in childcare centres and in primary and middle schools. Also, sufficient evidence has been found for multicomponent, community-wide campaigns. Such campaigns use a defined name or
logo and focus on a specified geographical region. The campaigns work through combining several strategies to increase sun protection behaviour, for instance mass media campaigns, individual directed strategies and policy changes.
The Scandinavian country of Denmark has success-fully used multicomponent, community-wide pre-vention campaigns during the last years. The Danish Sun Safety Campaign has run campaigns like “Flyt hyggen ind i skyggen” and “Lidt skygge skader ikke på ferien” (see Figure 6), that used digital dialogue, partnerships with travel agencies, mass media etc. to promote a sun safe behaviour to the Danish
1.3 PREVENTION
1.3.1 PRIMARY PREVENTION
Primary prevention is defined as preventing a disease by lowering exposure to risk factors, or by increasing resistance to risk factors. In the case of melanoma, primary prevention is equal to reducing excessive amounts of UV radiation from the sun and from sunbeds. The use of sunscreen is also a form of primary prevention. The goal of primary prevention is to prevent the forming of a melanocytic neoplasm.
Reducing sun exposure
As previously mentioned, there is consensus in the research community about UV radiation as the most important underlying cause of melanoma. Thus, preventive strategies include avoiding excessive sun exposure (27). But on the other hand, there is no
con-sensus about the exact amount or duration of UV ra-diation that causes melanoma. Since no consensus has been reached on whether there are UV radiation doses that balance health benefits and unfavourable health effects, it becomes difficult for the public to navigate between mixed messages. One day, media will promote sun protection to prevent skin cancer and the next day the public will be warned about
Vitamin D deficiency caused by too little sun exposure
(74). As an example, a recent Swedish study attracted
some media attention, suggesting that avoiders of sun exposure showed a reduced life expectancy of 0.6-2.1 years, compared to the study group with the highest sun exposure (75) . This in an interesting idea,
suggest-ing that the positive effects of sun exposure might be mediated by Vitamin D. But the reduced life expec-tancy may have been due to confounding factors not adjusted for, such as lack of physical activity. This was also acknowledged in the study (76).
In fact, there is sufficient evidence that the sun cer-tainly should not be avoided completely. Humans need Vitamin D, synthesized in the skin upon expo-sure to UVB radiation. Vitamin D is essential to the immune system and to bone development. Vitamin D deficiency has been associated with increased risk of, among others, common cancers and cardiovas-cular disease (77). Thus, a humble attitude to adopt
until further research on safe dosages of UV radia-tion is available would be to be exposed to the sun in moderation. Currently, the guidelines from the Swedish Radiation Safety Authority regarding sun protection is summarized in Figure 5 (78):
››› PROTECTIVE CLOTHING, A HAT AND SUN GLASSES ARE THE BEST OPTIONS FOR
SUN PROTECTION
››› STAY IN THE SHADE IN THE MIDDLE OF THE DAY (11 AM-3 PM)
››› USE SUNSCREEN ON BODY PARTS NOT PROTECTED BY CLOTHING
public (80). Continuous evaluation, including
pub-lished research studies has also been an important part of the Danish strategy. Denmark has about the same ambient UV radiation levels as Sweden, and may thus be suitable for comparison with Swedish
circumstances. However, substantially more eco-nomic resources have to be allocated to skin cancer prevention in Sweden to make it possible to set up an organisation similar to the Danish Sun Safety Campaign.
Figure 6. “Lidt skygge skader ikke på ferien” – a multicomponent, community-wide campaign set in Denmark in 2012. Copyright permission from the Danish Sun Safety Campaign
Solcreme
Solhat
Sk
yg
ge
LIDT
SKYGGE
SKADER
IKKE på
fERIEn
Solcreme er ikke altid nok. Brug skyggen og nedsæt din risiko for at få kræft i huden
Australia is another good example of a country, which has been a forerunner in preventing skin cancer. Pri-mary prevention interventions have been present there since almost forty years, much as a result of the country’s high melanoma incidence (3, 81). One
well-coordinated Australian example of a primary preventive intervention is focused on an education-al setting, namely primary and middle school-based
interventions within the SunSmart programme (82,
83). The programme has comprehensive coverage in
several Australian states, and works through, among others, teaching school children about sun safety, implementing sun safety policies and providing outdoor shade structures. The introduction of a primary prevention programme like “SunSmart” in Swedish child care centres and schools could be a possible way of preventing dangerous sun-related behaviour. No doubted, the programme would have to be adapted to Swedish circumstances regarding for instance ambient UV radiation levels. Further, it would demand vast economic recourses, a huge organization and a long-term commitment. But, the outlook for success of such a programme is very much supported by the above-mentioned research on suitable target groups (79). Also, several studies
have reported on the cost-effectiveness of the “Sun-Smart” programme, with one study estimating that every dollar invested would give a return of AU$ 2.30 (84, 85). The problem lies in convincing Swedish
policymakers to allocate economic resources for skin cancer prevention right now, although the de-creasing morbidity and mortality rates will be first visible after several decades.
The strategic primary prevention activities in Aus-tralia, resulting in lower levels of sun exposure in the younger populations, may have contributed partly to the recent stabilization and drop in incidence trends (2). However, this may not be the entire truth.
Another contributing factor that has been proposed is the introduction of information technology. In Australia, as well as in numerous other countries in the world, information technology has lead to more hours spent in front of a computer screen for young people, instead of playing outdoors. Also, the decreasing incidence trends have been suggested to be due to immigration of populations at lower risk of melanoma, due to their darker skin type (86). Others
have argued that the effect of immigration is too
small to lead to the observed decrease (87). Skin cancer awareness
For a lot of Swedes, a suntan still symbolizes a healthy, rich and fashionable lifestyle. The love of the sun among Swedes is a true challenge when trying to promote sun protection behaviours and in-crease skin cancer awareness. As an example, there is evidence that Swedes are more prone to high-risk sun behaviour in comparison with other countries. In 2010, two international studies on sun protection behaviour and attitudes towards tanning were pub-lished (88, 89). The results of the studies originated
Not only is there consensus in the research com-munity about UV radiation as the major cause of melanoma, there is also widespread knowledge in the Swedish public about this fact. According to a 2005 survey from the Swedish Radiation Safety Authority, 98% of the participating Swedes knew that there is a connection between the UV-rays of
the sun and skin cancer (90). The same authority
performed a web survey in 2016, showing that despite knowledge of the harms of the sun, 92% of the participating Swedes stated that they burn in the sun. The reason for sun exposure mentioned in the survey were foremost, with 58% of respondents, that it makes you feel good. Also, 83% still found a suntan attractive (91).
Although a lot of Swedes still burn in the sun and express a high level of preferred tanning, there are also promising results regarding increasing sun pro-tection in the Swedish public. The previously men-tioned web survey by the Swedish Radiation Safety Authority also showed that 4 out of 10 respondents spent less time in the sun in 2016, compared to five years before (91). Another report from the Swedish
National Board of Health and Welfare shows that the
proportion of 4-year-old and 12-year-old children who are protected from the sun in any way during summertime increased significantly between the years 2003 and 2011 (92). Moreover, a study from the
south of Sweden has showed increased self-reported sun-protective actions among parents of 7-year-old children, between the years of 2002 and 2007. The same study also showed a significantly lower count of the number of nevi per square metre body surface in 2007, compared to in 2002. In this study, the nevi count was used as a proxy for sun exposure (93). Avoiding sunbeds
Brazil was the first country in the world to outlaw sunbeds for aesthetic use in 2009. This action was trailed by a total ban in Australia in 2016. The ban in Australia followed some years after the highly publi-cised death of a 26-year-old skin cancer victim called Clare Oliver, who attributed her disease to the use of sunbeds (94, 95). The death of Clare Oliver started
a debate in the media and increased perceptions of the dangers of sunbeds in the Australian population. The media coverage, along with long-standing work from community advocacy groups, eventually led to sunbed legislations (96). Another illustration of
Figure 7. Computer-generated photos of people with varying levels of suntan. Swedish participants in a study by Bränström et al.
(2010), had the highest preferred level of tan of all participating countries, choosing the bottom left photo (88) media attention increasing public awareness was
when the American actress Angelina Jolie in 2013 announced that she had had a double mastectomy because of an inherited mutation in the BRCA1 gene. The announcement brought direct focus on inherit-ed risk of breast cancer in the public (97). To sum up,
media attention on a celebrity or on a victim of dis-ease can have a catalytic effect and a large impact on public awareness. If the opportunity presents itself in Sweden in the future, authorities and advocacy groups should try to reinforce the media coverage to increase skin cancer awareness.
Several other jurisdictions have enacted legislation to protect minors from sunbeds, including among
others Great Britain, France and Germany (98).
Among the Scandinavian countries, Norway has a ban in place to protect minors, <18 years of age, but this will be fully enforced first in 2017, when an age verification system must be in place at the sunbed facilities (99). Denmark, on the other hand, does not
have a restriction for minors using sunbeds (100).
Despite this, a survey has shown that Denmark has succeeded in decreasing the proportion of sunbed users aged 15-25 from 41% to 14% between 2008 and 2015. The drop in sunbed users aged 15-64 was from 25% to 11 % during the same years. The decreasing sunbed use in the Danish population may be an effect of another multicomponent community-wide campaign by the Danish Sun Safety Campaign: ”Sluk solariet” (101).
Already in 2009, the Swedish Radiation Safety Au-thority recommended regulation of sunbed facilities open to the public, including the prohibition of use for minors (102). Since 2010, the same authority
discourages municipalities from having sunbeds in sports and recreation facilities (78). As this thesis was
being completed, on October 27, 2016, the Swedish government finally announced a ban restricting minors from using sunbeds, to be fully enforced in 2018 (102-104). After the ban for minors is passed, it
would be advisable to keep studying sunbed use to see if the rates are dropping. Previous research has shown that legislation has the potential of reducing a vast number of melanoma deaths (105). As an
ex-ample, it was estimated that one in six melanomas in young Australians (18-29 years of age) could be prevented if sunbeds were not available (106). Most
likely, the sunbed ban for minors will have an impact on reducing the number of melanoma deaths also in Sweden. Consequently, a complete sunbed ban for cosmetic use would have an even higher impact.
Sunscreen
Sunscreen is a substance, usually a cream or a lo-tion, designed to protect from excessive sun expo-sure. Physical sunscreen works through reflecting and scattering UV radiation and visible light, while chemical sunscreens absorb UV radiation in the skin. Sunscreen can protect both against UVA and UVB radiation, depending on the substance used
(107). There is risk of sunscreens being used to
in-crease sun exposure, so that sunbathers can stay longer in the sun without burning. Also, sunscreens are often used inadequately, with smaller amounts than recommended and too few applications (108).
The use of sunscreen to prevent melanoma has long been controversial (109). However, the famous
Nambour trial, named after a town in Queensland, Australia, has shown that regular use of sunscreen may have protective effects (110). The study showed
a substantial reduction of invasive melanomas for persons using sunscreen, when compared to mela-noma in situ. Furthermore, the invasive melamela-nomas in the persons using sunscreen were significantly thinner. There was also a 50% reduction in prima-ry melanomas in sunscreen users, although only reaching borderline significance. Further research in this area is needed.
1.3.2 SECONDARY PREVENTION
Secondary prevention is defined as early detection and treatment of a disease. In the case of melanoma, secondary prevention includes skin self-examina-tion by patients and early detecself-examina-tion by physicians (e.g. screening activities). Skin self-examination and early detection by physicians lead to the excision of thinner tumours. Thin tumours have a better prognosis and increased survival rates compared to thicker tumours (111). Increased survival is the goal
for secondary prevention.
Skin self-examination
Fortunately, melanoma is a type of cancer that, in most cases, is easily detectable on the skin sur-face. Recommending individuals to examine their
own full body skin surface at home, with regular intervals, has proven to be a successful means
of reducing melanoma mortality (112). Thus, skin
self-examination is a recommendation that has been widely advised to the public (see Figure 8) (113).
1. Look at your face, including nose, lips, mouth, on and behind the ears.
2. Check your scalp, using a comb to part your hair in layers. Men : in case of baldness, check your scalp thoroughly.
3. Check your hands, front and back and in between the fingers.
4. Next, focus on the neck, chest and upper body. Women : check between and
underneath your breast.
5. Lift your arm to check your upper arm and armpits.
6. Use a small mirror to check the back of your neck and your back.
7. Check your buttocks and the back of your legs. Finish by checking between toes and the soles.
Make a habit of checking your skin once a month.
So screen your entire body, front and back, preferably
in front of a full-length mirror.
And remember
At the first sign of something out of
the ordinary, please consult your
dermatologist.
More information about the different
kinds of skin spots, their signification
and treatment, on
www.euromalanoma.org
Figure 8. Skin self-examination guidelines, as recommended by the campaign “See it, stop it!” from Euromelanoma.org in 2013. Euromelanoma.org is a European campaign for skin cancer prevention, with the goal to give information to everybody on skin cancer prevention, early detection and treatment. Copyright permission from Euromelanoma.org
The majority of individuals (57% in one study) de-tect their own melanomas, as opposed to dede-tection by physicians (16%) and spouses (11%) (114). Women
are better at detecting their own melanomas than males (69% versus 47%). Although individuals may be capable of detecting their own melanoma, there is sometimes a delay to seek medical advice. This is commonly referred to as patient’s delay, which is defined as the time interval from the appearance of symptoms until the patient seeks medical care. Pa-tient’s delay can be caused by a lack of knowledge, fright for the diagnosis, and denial (115). Patient’s
delay occurs regardless of the fact that many people are well-aware that early detection may improve the outcome. One study found that in Sweden and Australia, over 90% of melanoma patients had this knowledge (116).
Early detection by physicians (e.g. screening activities)
The time interval from the patient seeking medical care until diagnosis and treatment is known as tor’s delay. One important factor for influencing doc-tor’s delay is lack of knowledge (i.e. low diagnostic accuracy) (116, 117).
Visual, macroscopic examination of a suspicious skin lesion is one way of detecting a melanoma for health care professionals. However, the diagnosis of skin lesions could be further refined using dermos-copy (skin surface microsdermos-copy). In a meta-analysis, dermoscopy increased the sensitivity of the diag-nostic accuracy of melanoma significantly com-pared to visual examination. No significant increase in the specificity could be determined (118). Total
body photography combined with digital dermo-scopic monitoring is a supportive technique used for high-risk individuals where the entire skin surface is photographed and additional macroscopic and der-moscopic photos are taken of selected lesions and monitored (119, 120). Digital dermoscopic monitoring,
comparing current and previous dermocopic imag-es of melanocytic limag-esions to detect subtle changimag-es, has proven to be helpful for detecting very early melanomas where specific criteria for melanoma are not yet present (120).
In the era of information technology, another new promising method has appeared to assist in the
early detection of melanomas – teledermoscopy referrals. This is defined as attaching dermoscopic photographs to referrals for evaluation by a derma-tologist. The use of dermoscopic photographs for triage of referrals has proven to be a useful method for shortening waiting times in the melanoma care
pathway (121). For Western Sweden, the
implemen-tation of teledermoscopy referrals is awaited during 2017.
There is money to be saved by channelling resourc-es towards dermatologists examining suspicious skin lesions, instead of general practitioners. The reason for this is that dermatologists have a higher accuracy when diagnosing melanocytic skin lesions
(117, 122, 123). As a result from better diagnostic
accura-cy, the number of skin lesions needed to excise to detect a melanoma decreases. Lowering the rates of unnecessary excisions of benign skin lesions result in reduced costs (124). Unfortunately there is a lack
of dermatologists in Sweden, resulting in lower ac-cess to expert consultations regarding suspicious skin lesions (125). Moreover, there is a national lack
of pathologists, possibly resulting in long delays for pathological reports for excised lesions.
Screening of melanoma can be divided into mass screening of an entire population, opportunistic screening and screening of high-risk populations. Screening is per definition performed on asymp-tomatic populations.
The principles for mass screening of diseases was developed by Wilson et al. in a publication by the World Health Organization in 1968 (126). Many, but
The largest mass screening programme in the world so far was launched in 2008 in Germany, aimed at the entire population >35 years of age. The programme started after initial study data from the state of Schleswig-Holstein showed an instant decline in melanoma mortality rates. However, the decline in mortality was transient and might have been due to awareness effects, selection bias, data artefacts or natural fluctuations of the death rates
(127). In conclusion, there is no sufficient evidence
for implementation of mass screening activities of an entire adult population. Consequently, this is also the statement from the Community Preventive Services Task Force under the United States Depart-ment of Health and Human Services (128).
Opportunistic screening is understood as screening for melanoma when patients present to a physician for other purposes. For instance, total body skin examination is valuable in patients presenting with localized dermatologic conditions, since this can detect melanomas that would have been otherwise overlooked. In one study, 0.3% of patients seeking for a localized dermatologic condition were found to have a melanoma on covered body parts when screened with total body skin examination. Total body skin examination should be considered in, among others, older patients and in patients con-sulting for any kind of skin tumour (129).
Opportunis-tic screening could also be performed together with a routine physical exam by a general practitioner. Screening of high-risk populations could also be directed towards individuals with a risk factor for melanoma development. There are many exam-ples of this in the literature, including screening of populations with personal or family history of mel-anoma and populations of men of older age groups
(130-133). Some of these high-risk screening activities
favoured from combining several risk factors, which increased the risk of melanoma development among the participants. Screening of high-risk pop-ulations has, unlike mass screening, been proven to be cost-effective (84). Therefore, high-risk population
screening is something that could be used more in clinical practice in Sweden. Future screening strate-gies might also benefit from the use of new informa-tion technology (121, 134, 135).
1.4 STAGING AND
CLASSIFICATION
1.4.1 STAGING
Worldwide, the American Joint Committee on Cancer (AJCC) staging system is used for cutaneous malig-nant melanoma (see Figure 9) (111). The AJCC staging
system was updated in 2009 and is based on the TNM Classification of malignant tumours. The TNM system describes whether the cancer has spread to the lymph nodes or if it has metastasized, assigning a letter and a number to describe the primary tumour (T), the nodes (N) and metastases (M).
7th ED I T I O N
Primary Tumor (T)
TX Primary tumor cannot be assessed (for example, curettaged or severely regressed melanoma)
T0 No evidence of primary tumor
Tis Melanoma in situ
T1 Melanomas 1.0 mm or less in thickness
T2 Melanomas 1.01–2.0 mm
T3 Melanomas 2.01–4.0 mm
T4 Melanomas more than 4.0 mm
NOTE: a and b subcategories of T are assigned based on ulceration and number of mitoses per mm2, as shown below:
T THICKNESS
CLASSIFICATION (mm) ULCERATION STATUS/MITOSES
T1 ≤1.0 a: w/o ulceration and mitosis <1/mm2
b: with ulceration or mitoses ≥1/mm2
T2 1.01–2.0 a: w/o ulceration b: with ulceration T3 2.01–4.0 a: w/o ulceration b: with ulceration T4 >4.0 a: w/o ulceration b: with ulceration
Regional Lymph Nodes (N)
NX Patients in whom the regional nodes cannot be assessed (for example, previously removed for another reason)
N0 No regional metastases detected
N1-3 Regional metastases based upon the number of metastatic nodes and presence or absence of intralymphatic metastases (in transit or satellite metastases)
NOTE: N1–3 and a–c subcategories assigned as shown below:
N NO. OF
CLASSIFICATION METASTATIC NODES NODAL METASTATIC MASS
N1 1 node a: micrometastasis1
b: macrometastasis2
N2 2–3 nodes a: micrometastasis1
b: macrometastasis2
c: in transit met(s)/satellite(s)
without metastatic nodes N3 4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s)
ANATOMIC STAGE /PROGNOSTIC GROUPS Clinical Staging3 Pathologic Staging4
Stage 0 Tis N0 M0 0 Tis N0 M0 Stage IA T1a N0 M0 IA T1a N0 M0 Stage IB T1b N0 M0 IB T1b N0 M0 T2a N0 M0 T2a N0 M0 Stage IIA T2b N0 M0 IIA T2b N0 M0 T3a N0 M0 T3a N0 M0 Stage IIB T3b N0 M0 IIB T3b N0 M0 T4a N0 M0 T4a N0 M0 Stage IIC T4b N0 M0 IIC T4b N0 M0 Stage III Any T ≥ N1 M0 IIIA T1-4a N1a M0 T1-4a N2a M0 IIIB T1-4b N1a M0 T1-4b N2a M0 T1-4a N1b M0 T1-4a N2b M0 T1-4a N2c M0 IIIC T1-4b N1b M0 T1-4b N2b M0 T1-4b N2c M0 Any T N3 M0 Stage IV Any T Any N M1 IV Any T Any N M1 Notes
1 Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).
2 Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension. 3 Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should
be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
4 Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete
lymphadenectomy. Pathologic Stage 0 or Stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes. Definitions
Distant Metastatis (M)
M0 No detectable evidence of distant metastases
M1a Metastases to skin, subcutaneous, or distant lymph nodes
M1b Metastases to lung
M1c Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH
NOTE: Serum LDH is incorporated into the M category as shown below:
M CLASSIFICATION SITE SERUM LDH
M1a Distant skin, subcutaneous, or nodal mets Normal
M1b Lung metastases Normal
M1c All other visceral metastases Normal
Any distant metastasis Elevated
A m e r i c a n J o i n t C o m m i t t e e o n C a n c e r
Melanoma of the Skin Staging
Financial support for AJCC 7th Edition Staging Posters
provided by the American Cancer Society Co
py rig ht 2 00 9 A m eri ca n J oin t C om m itt ee o n C an ce r • P rin te d w ith p er m iss ion f ro m t he A JC C.
Melanoma in situ (Stage 0)
Melanoma in situ is defined as a melanoma limited to the epidermis, not invading the dermis. The term in situ translates to “in place” in Latin. See Figure 10 for a photo of a melanoma in situ. Melanoma in situ is classified as Tis histopathologically and as stage 0 clinically.
Melanoma has been shown to have a radial and a vertical growth phase. First, the tumour grows radi-ally, spreading only in the epidermis. Eventuradi-ally, if the lesion is not excised, the tumour moves on to a vertical growth phase, invading the deeper layers of the skin – the dermis (136).
Stage I and II (the T-stage)
Stage I and II melanomas are both clinical stages of localized disease, equal to an invasive primary tu-mour, without signs of lymph node involvement or metastases. The clinical stages I and II will depend on the histopathological T-stage.
The histopathological factors determining the T-stage in localized disease are the Breslow thick-ness in millimetres (describing the distance between the upper layer of the epidermis and the deepest point of penetration of a malignant melanoma), the presence or absence of epithelium ulceration and the mitotic rate. The absence of ulceration is classi-fied with the letter “a” after the T-stage, whereas the presence of ulceration adds a “b” to the T-stage. The mitotic rate determines how fast-growing the cells in the melanoma are, and is used in the T1 category
(137). The cut-off for defining T1b melanomas
(inde-pendently of whether there is ulceration or not) is a mitotic rate of ≥1 mitosis/mm2(111).
The Breslow thickness divides the melanomas of stage I and II into T-categories: Tis (in situ), T1 (≤1.0 mm), T2 (1.01–2.0 mm), T3 (2.01–4.0 mm) and T4 (>4.0 mm). The Breslow thickness at diagnosis de-pends on the rate of growth and the time of develop-ment of the tumour. Thus, T1a-b and T2a melanomas define a clinical stage I disease whereas T2b, T3a-b and T4a-b melanomas result in a clinical stage II. In rare cases, when mitotic rate cannot be deter-mined in the histopathological report, the Clark level of anatomic invasion comes into consideration in the staging system. The Clark levels of invasion are defined as follows: level I – melanoma only in the epidermis; level II – invasion into the papillary der-mis; level III – expansion into the border between the papillary and the reticular dermis; level IV – invasion into the reticular dermis and level V – invasion into the subcutaneous fat.
Figure 10. Melanoma in situ on the back of a patient. Photo: John Paoli
Thin melanomas
Within stage I-II, there is a further, commonly used definition of melanomas based solely on the tumour thickness, namely the division into thin, intermedi-ate and thick lesions:
›››
Thin melanomas have a Breslow thickness of ≤1 mm
›››
Intermediate-thickness melanomas have a Breslow thickness of 1.01-4 mm
›››
Thick melanomas have a Breslow thickness of >4 mm
Much of the increase in melanoma incidence in the world is owed to an increase in thin melanomas (2, 138-141). This is true also for the Swedish melanoma
population in recent years, where a shift towards thinner tumours can be seen. During 2007-2011, 50.7% of all melanomas among men and 57.4% among all women in Sweden were thin tumours, compared with 48.4% among men and 57.1% among
women during 1997-2001 (141). During the limited
time period of 2002-2006, there was an unexplained tendency in Sweden towards a higher proportion of thick tumours (>4 mm) among women and among older men. However, during 2007-2011, this shifted back towards thinner melanomas.
Not only thin tumours have increased proportion-ally, but an incidence change of melanoma in situ has also been reported in Sweden. During the years 2009-2013, melanoma in situ rates in men increased from 24 to 32 per 100,000 person-years (Swedish standard population year 2000). Compared to Swe-den as a whole, the inciSwe-dence in men increased from
14 to 24 per 100,000 person-years (14). Although
there has been an increase in the melanoma in situ rates in Sweden, the increase might not be as high as reported. The National Board of Health and Welfare has recently acknowledged the misclassification of dysplastic nevi with severe atypia as melanoma in situ in their publication “Cancer Incidence in Swe-den 2014” (10). This falsely increased the number of
newly diagnosed melanoma in situ with as much as 26% in 2014 (unpublished data).
The increasing proportion of thin melanomas has
been attributed to a true increase in melanocytic neoplasms, to early detection and to diagnostic drift (5, 138-140, 142). Melanoma survival is closely
con-nected to tumour thickness, with excellent survival rates reported for thin tumours (111, 143). However,
there have been reports of a difference in survival rate within the group of thin melanomas, with lower rates for tumours ≥0.75 mm (143-145). The original
cut-off in thickness developed by Breslow was >0.75 mm, but since 2002 the cut-off for thin melanomas is 1 mm (111, 137).
Because of the excellent overall survival rates for patients with thin melanomas, these have been somewhat overlooked when investigating the bur-den of melanoma mortality. Since thin lesions have become so much more common, a recent study from Queensland, Australia has shown that in this population more people die from thin melanomas than from thick lesions (>4 mm) (146). In that study,
between the years 2005-2009, thin melanomas constituted 68% of all melanomas and were attribut-able to 23% of the melanoma deaths, whereas thick melanomas constituted 3% of all melanomas and accounted for 14% of deaths. Another study from the United States, showed that 26% of all melanoma fatalities were attributable to thin melanomas (147).
Also, thin melanomas have been shown to consti-tute a large proportion of Years of life with disability and Years of life lost in the disease compared to oth-er melanomas (148). Altogether, these studies
exem-plify the need to better identify, already at the time of diagnosis, the subset of patients with thin mela-nomas that will eventually die from metastasized disease. Consequently, a more detailed prognostic classification of thin tumours is desirable.
If thin melanomas could be classified in more de-tail according to prognosis, these patients could be monitored closely in follow-up programmes, with imaging techniques or sentinel lymph node biopsies. (See chapter 1.6.1 for a definition of sentinel lymph node biopsies.) And if patients with high-risk melanomas ≤1 mm were monitored more closely, treatment could be offered earlier. Such treatment could include metastasis surgery and the new ther-apies for metastasized melanoma that have revolu-tionized the management during the past few years
